Pyrazinylthioamides

ABSTRACT

Ethane thioamides disubstituted in 2-position by Het and R-Het being 2-pyridyl, 2- and 4-pyrimidyl, 2-pyrazinyl, 2- and 4thiazolyl, which are optionally substituted, and -R being loweralkyl having up to six carbon atoms inclusive when Het is 2pyridyl, and when Het is other than 2-pyridyl, R is then, loweralkyl having up to six carbon atoms inclusive, hydrogen, phenyl, halophenyl, lower alkyl-phenyl or lower-alkyloxy phenyl. These compounds possess antisecretory and ulceroprotector properties.

ite States Patent [72] inventors [21 Appl. No. [22] Filed [45] Patented[73] Assignee Medicale Suresnes, France [32] Priority July 10, 1968 [3 3Great Britain [31] 32,821/68 [54] PYRAZINYLTHIOAMIDES 4 Claims, NoDrawings [52] US. Cl 260/250, 260/2565, 260/2943, 260/306.8, 424/250,424/263, 424/251 [51 Int. Cl C07d 5l/76, e r C07d 51/36 [50] Field ofSearch a. 260/250 [56] References Cited UNITED STATES PATENTS 3,415,82812/1968 Sasse et al 260/250 Primary Examiner-Nicholas S. RizzoAttorneys-Gordon W. Hueschen and Hueschen and Kurlandsky ABSTRACT:Ethane thioamides disubstituted in 2-position by Het and RHet being2-pyridyl, 2- and 4-pyrimidyl, 2-pyrazinyl, 2- and 4-thiazolyl, whichare optionally substituted. and -R being lower-alkyl having up to sixcarbon atoms inclusive when Het is Z-pyridyl, and when Het is other than2-pyridyl, R is then, lower-alkyl having up to six carbon atomsinclusive hydrogen, phenyl, halophenyl, lower alkyl-phenyl orlower-alkyloxy phenyl.

These compounds possess antisecretory and ulceroprotector properties.

I PYRAZINYLTHIOAMIDES The present invention provides thioamides ofgeneral formulal Het NH; (I)

lower-alkyl having one to six carbon atoms inclusive,

hydrogen, phenyl, monoand poly-halo-phenyL-monoandpoly-lower-alkylphenyl, and mono-. and poly-lower-alltyloxyphenylradicals wherein the alkyl groups have one to five carbon atomsinclusive.

The present invention also provides physiologically tolera ble additionsalts of the derivatives of general formula I, especially salts withstrong acids.

Furthermore, all the compounds of general formula 1 possess anasymmetric carbon atom and thus-exist in the form of optical isomers.Thus the present invention also provides optical isomers of thecompounds of formula I and their physiologically tolerable acid additionsalts.

The compounds of the present invention maybe prepared by reacting adisubstituted acetonitrile of general formula ll Hels (11 in which R andHet have the meanings given above, with hydrogen sulfide in anappropriate solvent.

The reaction is generally effected in a basic solvent, for example amixture of pyridine-triethylamine, preferably at a temperature withinthe range of from 20 to 100, C.

The disubstituted acetonitriles of general formula 11 are themselvesprepared, from the corresponding monosubstituted acetonitriles,according to known methods such, for example, as method ofC. D. Gutscheand H. W. Voges, J. Org. Chem. 32, No. 9, 2,685+89 1967), or by directsubstitution of the corresponding monosubstituted .acetonitriles, or byothers appropriate known methods.

The derivatives of general formula I of the present invention are newand possess valuable pharmacological and therapeutic properties. Theyespecially exert an inhibitory effect on acid and peptic gastricsecretions and afford protection against gastroduodenal ulcers whilstbeing devoid of anticholinergic action.

These activities were demonstrated by the following tests:

1. Ulcer of restrain (S. Bonfils et al.: Rev. Fr. Et. Clin. Biol.

et al. Gastroent. 5, 43

'8. Technique of Ghosh and Schild (Brit. J. Pharm. 13, 54

(1958)). When administered at doses of 5 to mgJkg. intravenously in therat, the new compounds inhibit to 70 of the increase of gastric acidityprovoked by the secretionstimulant pentagastrine.

ties, decreasing acid as well as pepsin secretion. Doses of 5 toMoreover, it was demonstrated by the method of test-meal of A. F. Green(Brit. J. Pharm. 14, 27 (1959)) that the new compounds have nosubstantial eflect on the gastrointestinal motricity.

Finally, the new derivatives have no action on the autonomic nervoussystem, nor on the central nervous system.

The toxicity of the compounds of the invention is very low and the LD,is situated between 500 and 2,000 mg./kg. in mice by the oral route.

The above described pharmacological properties and the low toxicityenable the use of the new thioamides in therapy and especially in thetreatment of gastroduodenal ulcers and gastric hypersecretion.

The present invention further provides pharmaceutical preparationscomprising a compound of the general formula I or one of itsphysiologically tolerable salts in admixture or conjunction withpharmaceutically suitable carriers for oral, rectal or parenteraladministration.

Such suitable pharmaceutical carriers are, for example, distilled water,starch, talc, glucose, lactose, cocoa butter, etc... in order to obtainsuitable pharmaceutical forms such as, for example, tablets, dragees,capsules, suppositories or solutions.

The doses may vary from 50 to 500 mg., l to 5 times per day.

The following examples illustrate the invention. The melting points aredetermined on a Kofler block (BK) or on a Kofler heating bench under amicroscope (MK).

EXAMPLE 1 Eight grams of 2-( 2-pyridyl)-butane-nitrile, boilingpoint/0.1 mm. 60-65 C., prepared from 2-(2-pyridyl)- acetonitrileaccording to the method of C. D. Gutsche and H. W. Voges, J. Org. Chem.32, No. 9, 2685-89 (1967), dissolved in 5.6 g. of triethylamine and 8 g.of anhydrous pyridine, were saturated with dry gaseous H 8. The reactionmixture was heated to C. in a sealed tube and kept at this temperaturefor 15 hours.

The mixture was subsequently diluted with water and then extracted withchloroform. The chloroform phase was washed with water and then dried.The chloroform was then evaporated and the solid residue recrystallizedfrom benzene. Six grams of dl-2-(Z-pyridyl)-butane-thioamide, meltingpoint (BK) l08l09 C., were obtained.

Six milliliters of 4 N hydrogen chloride solution in either were addedto 4 g. of dl-2-(Z-pyridyl)-butane-thioamide dissolved in ml. ofethanol. The mixture was evaporated to dryness. The residue wasrecrystallized from a mixture of 50 ml. of ethyl acetate and 40 ml. ofethanol. 3.9 g. of dl-2-(2- pyridyl)-butane-thioamide hydrochloride wereobtained; instantaneous melting point (BK) l80-l 8 1 C.

The following compounds were prepared according to the process describedin example 1, the starting materials either being known or beingprepared from known materials according to methods known per se.

EXAMPLES 2-l5 5. dl-2-(2-pyridyl)-4-methyl-pentane-thioamide, meltingpoint (BK) l38-l40 C. prepared by reaction of H 8 with 2-(2pyridyl)-4-methyl-pentane-nitrile, boiling point/0.1 mm. 76-80 C.

6. dl-2-(2-pyridyl)-octane-thioamide, melting point (BK) 75-76aL C.prepared by reaction of H 5 with 2-( 2-pyridyl)-octane-nitrile, boilingpoint/0.04 mm. 97l00 C.

7. dl-2-(Z-pyridyl)-pent-4-ene-thioamide, melting point (BK) 7475aL C.hydrochloride l40-l4l C. prepared by reaction of H 5 with2-(2-pyridyl)-pent-4-ene-nitrile, boiling point/0.3 mm. 72-74 C.

8. -d1-2-(2-pyridyl)-propane-thioamide, instantaneous melting point (BK)of the hydrochloride l63-l66 C., prepared by reaction of H 8 with2-(2-pyridyl)-propane-nitrile, boiling point/0.05 mm. 5054 C.

9. dl-2-(Z-pyrimidyl)-2-phenyl-ethane-thioamide, melting point (BK)l85-l 86 C., prepared by reaction of H 8 with 2-(Z-pyrimidyl)-2-phenyl-ethanenitrile, boiling point/0.03 mm. l32-l40 C.

l0. dl-2-(2-pyrimidyl)-2-(4-chlorophenyl)-ethane-thioamide melting point(MK) l50-l54 C. with crystallization around 148 C., prepared by reactionof H 5 with 2-(2-pyrimidyl)-2- (4-chlorophenyl)-ethane-nitrile, boilingpoint/0.2 mm. l5S-l 60 C.

instantaneous melting point (BK) of the ll.dl-2-(4,6-dimethyl-2-pyrimidyl)-ethane-thioamide. melting point (BK)l49l 50 C.. prepared by reaction of H 5 with2-(4.6-dimethyl-2-pyrimidyl)-ethane-nitrile. melting point (BK) 8l C.l2. di-2-(2-pyrazinyl)-2-phenyl-ethune-thioumide melting point (BK)l42l43C. prepared by reaction of H,S with 2-(2-pyrazinyl)-2-phenyl-ethune-nitrile. melting point (BK) I33- I 34 C.l3. dl-2-(2-pyrazinyl)-ethane-thioamidc. melting point (BK) l l2l l4 C.,prepared by reaction of H 5 with 2-(2-pyrazinyl)-ethane-nitrile, boilingpoint/l 8 mm. l45l 50 C. 14. dl-2-(2-pyrazinyl)-butane-thioamide,melting point (MK) 8890 C., prepared by reaction of H 5 with2-(2-pyrazinyl)- butene-nitrile, boiling point/0.05 mm. 82-84 C. 15.dl-2-( 2thiazolyl)Z-phenyI-ethane-thioamide, melting point (BK) l25-l26C., prepared by reaction of H 8 with 2-(2-thiazolyl)-Z-phenyl-ethane-nitrile, boiling point/0.01 mm. 1 l5-l25 C.

We claim:

1. A compound selected from the group consisting of (A) thioamides ofgeneral formula wherein R is selected from the group consisting of loweralkyl having one to six carbon atoms inclusive. hydrogen, phenyl,halophenyl, lower-alkylphenyl and lower-alkoxyphenyl wherein alkyl hasone to five carbon atoms inclusive; and (B) physiologically acceptableaddition salts thereof with suitable acids.

2. A compound of claim 1 which is dl-2-(2-pyrazinyl)-butane-thioamide.

3. A compound of claim 1 which is dl 2-(2-pyrazinyl)-2- phenyl-ethanethioamide.

4. A compound of claim 1 which is di 2-(2-pyrazinyl)-2 ethane-thioamide.

CERTIFICATE OF CORRECTION Patent No. 3,624,085 Dated 30 November 1971Charles Malen et al.

Inventor(s) It is certified that error appears in the above-identifiedpatent and that said Letters Patent are hereby corrected as shown below:

[73] Assignee "Societe em nom Collictif Science Union Et Cie, SocietyFrancasie De Recherche Medicale" Societe en nom Collectif Science-Unio:et Cie. Societe Francaise de Recherche Medicale Col. 1, line "Z-pyridal"Page 1, line 18 Z-pyridyl Col. 1, line 55 "others" Page .2, line 8 otherCol. L, line 74 "the free Page 2, line 2] of the free Col. 2, line 4 "15to 70" Page 2, line 15 to 70 percent C01. 2, line (Formula in Example 1)Page 3, line 11 H C H c s CH-C f 3 n m I 2 N Col. 2, line (Example 1)Page 3, line 22 "either" ether 1M PO-fl 10-69 I USCOMM-DC 60376-P69 nUS, GOVERNMINT PRINTING OFFICE 199 0-165-314 Patent No.

Inventor(s) Dated 30 November 1971 Charles Malen, et a1.

It is certified that error appears in the above-identified patent andthat said Letters Patent are hereby corrected as shown below:

line 4 Col. 3, Page 3, line Col. 3, line Page 4, line Col. 3, line linePage 4, line Col. 3, line Page line Col. 3, line Page 4, line Col. 3,line Page 4, line Col. 3, line line Page 4, line Col. 3, line Page lineCol. 4, line line Page A, line same Col

33 (Example 2) 4 (Example 3) 20 (beginning of 9 (Example 5) 21 10(Example 5) 23 11 (Example 6) 26 13 (Example 7) 30, beginning of 16(Example 8) 39, end of line 22 (Example 10) 5, beginning of 28 (Example12) line, at end of line line Page 5, line 5 (Example 14) "2-(Z-pyridal) Z-(Z-pyridyl)...

"75 76aL C. 75 76 C.

"thioamide" thioamide,

-- dl-Z- "melting" melting "butene-" butane- M PC3-1051) (10-69)USCOMM-DC 60376-P69 r u s GOVERNMENY PRINTING OFFICE 1969 0-365-334CERTIFICATE OF CORRECTION 30 November 1971 Patent No. 3 a 624,085 DatedCharles Malen et a1.

Inventor(s) It is certified that error appears in the above-identifiedpatent and that said Letters Patent are hereby corrected as shown below:

Col. 4, line 15 (2thiazo1y1)2-". Page 5, line 7 (Example 15)(2-thiazolyl)2- Col. 4, Claim 1 FORMULA (See R&A dated October 31, 1969Claim 9 formula) N R ,s n I N CH C 2 Claim 3, Col. 4, line 1 "d1 2-"dl-2- Claim 3, Col 4, line 2 "-ethane thioamide.

-- -ethane-thioamide.

Claim 4, line 1 "d1 2- (2 pyrazinyl)-2" dl-Z- (2-pyraziny1)-2- Signedand sealed the 17th day of October 1972.

(SEAL) Attest:

EDWARD M.FLE'I'CHER,JR. ROBERT GOT'ISGHALK Attesting OfficerCommissioner of Patents M po'mso (0-69) USCOMM-DC suave-ps9 n U 5GOVERNMENT PRINTING OFFICE 969 0356-33

2. A compound of claim 1 which is dl-2-(2-pyrazinyl)-butane-thioamide.3. A compound of claim 1 which is dl 2-(2-pyrazinyl)-2-phenyl-ethanethioamide.
 4. A compound of claim 1 which is dl2-(2-pyrazinyl)-2ethane-thioamide.